The Clinical Genetics Branch (CGB) integrates molecular and clinical observations in cancer genetics into an interdisciplinary approach involving epidemiologic, clinical, genetic, behavioral, statistical and laboratory methods to define the role of susceptibility genes in cancer etiology. The primary goal of this research program is translate recent dramatic advances in molecular genetics into evidence-based management strategies for persons at increased genetic risk of cancer. The central research strategy relies upon the detailed and meticulous assessment of the individual members of cancer-prone families. The first major clinical research project undertaken by CGB represents the next stage in DCEG's long-standing commitment to the study of hereditary breast and ovarian cancer (HBOC). The first priority with regard to these families is to make clinical predictive genetic testing for BRCA1/2 mutations available to interested family members. All families have been notified of their mutation status, and the process of bringing interested family members to the Clinical Center for genetic risk assessment, counseling, genetic testing and results disclosure is now underway. Concurrently, we will mount a carefully-designed research protocol for these same individuals. This project will address issues related to breast cancer screening, early diagnosis, behavioral, educational and psychosocial dynamics related to the process of genetic risk assessment and testing, endogenous hormones as contributors to the risk of hereditary breast cancer, and decision-making by family members related to the use of tamoxifen as a breast cancer chemoprevention strategy. The Concept and Protocol related to this study are now under development. The first component of this study to begin patient accrual is a pilot study assessing mammography, MRI and PET imaging as screening tools for women at increased genetic risk of breast cancer. This protocol is actively underway. This project will also assess the impact of menstrual cycle timing on breast MRI imaging characteristics, and provide us with an opportunity to evaluate breast duct lavage, a new technique for obtaining breast duct epithelial cells, as an early diagnosis tool in this setting, and as a potential source of biological materials for molecular genetic studies. The hereditary breast/ovarian cancer project has also provided the opportunity to initiate development of a behavioral/psychosocial research program within CGB. This activity will target individuals at increased genetic risk of cancer, and will draw upon the expertise of recently-recruited staff, including a genetic counselor, a psychiatric social worker and a cancer genetics research nurse. This project is being developed with the support of senior behavioral investigators from NCI's Division of Cancer Control and Population Studies. Initial assessment will focus on the experience of subjects participating in the Breast Imaging Study. We anticipate extending this effort to explore a series of important issues among persons participating in the Inherited Bone Marrow Failure Syndromes Study. A study of the prevalence of BRCA1/2 founder mutations is nearing completion in a series of 1000 Ashkenazi Israelis with prostate cancer during 1994 - 1995. Preliminary analyses suggest a two-fold excess of prostate cancer among mutation carriers. No major differences in histopathology between mutation-related and mutation-unrelated have been identified. We are finishing laboratory studies to seek loss of heterozygosity at the BRCA1/2 gene loci in prostate cancer tumor tissue. These findings provide a more solid rationale for proceeding with a study of prostate cancer screening and prevention among the men from our HBOC families who are mutation carriers. Planning for this new project is in its beginning stages. Among the many pressing clinical issues in the management of women who carry mutations in BRCA1/2 is the appropriate role of prophylactic oophorectomy as a risk reduction strategy. In collaboration with investigators from the Gynecologic Oncology Group (GOG) and the Cancer Genetics Network, plans are well underway to mount a national, prospective follow-up study of genetically at-risk women who elect to undergo prophylactic oophorectomy. This will permit us to address such issues as: (a) what is the prevalence of clinically occult ovarian cancer at the time of prophylactic oophorectomy? (b) are there identifiable precursor lesions in the ovaries of genetically at-risk women? (c) what is the incidence of primary peritoneal carcinomatosis and breast cancer subsequent to this operation? and (d) how does this surgical procedure affect the quality of life for the women who elect it? Women who elect to retain their ovaries will be monitored with a novel ovarian cancer screening algorithm based on rate-of-change of CA125 levels over time. This study should begin accrual by the end of calendar year 2001. Our multidisciplinary research program targeting the inherited pediatric disorders which predispose to bone marrow failure, acute leukemia and, in adult survivors, solid tumors has just been submitted for IRB approval. Fanconi's Anemia is the prototype of these diseases, which also include dyskeratosis congenita, Diamond-Blackfan syndrome and Schwachman-Diamond syndrome. These rare disorders will be used as models for studying mechanisms of carcinogenesis in humans. In particular, we will analyze the possible role of HPV in the etiology of the oral cavity and female genital malignancies which occur excessively in this setting. Genotype/phenotype correlations will be performed. An effort will be made to determine if persons who are heterozygous (carriers) for deleterious mutations in the FA genes are at increased risk of cancer. We anticipate initiating patient accrual in early 2002. Plans to re-activate DCEG's interest in familial testicular cancer are well underway. We are actively collaborating with the International Testicular Cancer Linkage Consortium in a series of studies related to this rare familial cancer syndrome. CGB investigators have taken the lead in designing a central review of the testicular cancer pathology and a quantitative analysis of the occurrence of cancers other than germ cell tumors in the Consortium family set. Data collection related to these two projects should begin in early 2002. In addition, we are finalizing a concept related to accruing new testicular cancer families. These families will contribute DNA for positional cloning of the X-linked testicular cancer susceptibility gene TGCT1, and to permit genome scanning for presumed additional autosomal susceptibility genes as well. Interested families will be broght to the NIH Clinical Center for a more detailed, etiologically oriented, clinical/genetic/laboratory study of the type that has historically been done so well by DCEG investigators. The combination of breast cancer and colon cancer in different members of the same family seems to occur more often than can be accounted for by the known hereditary cancer syndromes. We are completing a literature review related to this association, which will serve as a basis for planning a family/genetic study of women with double primary cancers of the breast and colon in an effort to clarify this association. Evidence for an as yet unidentified cancer susceptibility gene will be sought. CGB is collaborating with the Genetic Epidemiology Branch in an effort to develop a comprehensive approach to the evaluation of families with lymphoproliferative malignancies. This will build on current studies of familial CLL, Waldenstrom's macroglobulinemia and non-Hodgkin's lymphoma. Opportunities have developed which may permit us to study familial multiple myeloma and familial acute leukemia. The goal is to design a research strategy that will allow us to explain the fact that the clustering of these cancers tends to be heterogeneous within families, rather than tumor type specific. We intend to study additional familial cancer syndromes which, thus far, have been inadequately evaluated. Under consideration at the present time are studies of familial gastric cancer and familial bladder cancer. CGB will also play a role, as needed, in the analysis of family history data collected as part of ongoing analytic epidemiology studies conducted by colleagues elsewhere within DCEG. The first such project entails an assessment of family history of cancer and level of Westernization as cancer risk factors in a population-based, case-control study of breast cancer in Asian American women. This is being done through a collaboration with investigators in the Epidemiology and Biostatistics Program, and the Genetic Epidemiology Branch. Preliminary results suggest a possible synergism between environmental risk factors and genetic risk factors in the etiology of breast cancer among women of Asian ancestry who migrate to the United States. CGB is also devoting significant attention and staff energy to the training of various health care professionals and researchers with an interest in clinical cancer genetics. Our first pre-doctoral candidate is nearing completing of her PhD thesis in epidemiology. She is analyzing the relationship between family history of breast cancer and the risk of developing either endometrial or ovarian cancer among women participating in DCEG's follow-up of the BCDDP cohort. We now have two post-doctoral cancer genetics fellows working with us, one a PhD in medical genetics and the other an MD, board-certified in medical oncology. We have recently been certified by the American Board of Genetic Counselors as an official clinical training site for genetic counselor graduate students who are enrolled in the joint NHGRI/Johns Hopkins University School of Public Health masters' program.